Background: B-cell non-Hodgkin lymphomas (B-NHL) are frequently characterised by deregulation of the B-cell leukaemia/lymphoma-2 (BCL2) family of anti-apoptotic proteins. Venetoclax is a BCL2-specific inhibitor approved for chronic lymphocytic leukemia (CLL), with activity in other B-cell malignancies in small cohorts. Venetoclax has been available for patients (pts) with relapsed/refractory B-NHL via the Abbvie compassionate access scheme or as off label treatment, however data regarding effectiveness in this setting are scarce. Methods: We performed a multicentre, international, retrospective study of the clinical outcomes and safety of pts with B-NHL (excluding CLL) who received venetoclax either as monotherapy or as combination treatment in Australia or Denmark between 7/2016 and 12/2018. Results: The baseline characteristics of the 24 eligible pts are summarised in the table (Figure 1a). Target daily dose varied from 400-1200mg and was reached in 77%. Among all pts, the objective response rate (ORR) was 35%, clinical benefit rate (SD/PR/CR) 65% and CR rate 8%; one patient each with MCL and transformed follicular lymphoma. The Waldenstrom macroglobulinaemia patient achieved a MR with monotherapy, improving to a PR when cyclophosphamide and dexamethasone were subsequently added. The ORR was 50% and 27% for pts treated with venetoclax combined with additional systemic therapy and monotherapy respectively. The ORR was 42% in MCL (ORR 66%, n=2 in those receiving combination treatment, and ORR 33%, n=3 in BTK inhibitor refractory pts) and 0% in DLBCL. 1/5 patients bearing TP53 aberrations (n=5 [MCL n=3, Richter's n=2]) had a response (PR). Median time on venetoclax, PFS and OS for all pts were 2.7, 2.4 and 3.1 months respectively (Figure 1b,c). 5 pts had a PFS >6 months (maximum 20.4 months), and 6 pts (25%) were alive at last follow-up, with 4 (17%) remaining on venetoclax. 75% (n=3) of these received concurrent therapy (ibrutinib n=2) and 25% (n=1) received monotherapy. Causes of death included progressive lymphoma (78%, n=14) and infection (11%, n=2). 10 (50%) discontinued therapy due to PD and 4 (20%) due to adverse events. The most frequent grade 3/4 adverse events were neutropenia(35%, n=6), febrile neutropenia(18%, n=3), tumour lysis syndrome (laboratory 33%, n=8 [MCL n=6, DLBCL n=1, Richter's n=1], clinical 8%, n=2 [MCL n=2]), thrombocytopenia (17%, n=4) infection (12%, n=3) and anaemia (8%, n=2), and diarrhoea (4%, n=1) Keywords: B-cell lymphoma; venetoclax. Disclosures: El-Galaly, T: Employment Leadership Position: Roche. Tam, C: Honoraria: Abbvie; Research Funding: Abbvie. Seymour, J: Consultant Advisory Role: Abbvie, Roche 7, Janssen; Honoraria: Abbvie, Roche 7, Janssen; Research Funding: Abbvie, Roche 7, Janssen; Other Remuneration: Abbvie, Roche 7, Janssen, (speaker). Cheah, C: Consultant Advisory Role: Roche, Janssen, Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Honoraria: Roche, Janssen, Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Research Funding: Celgene, Roche, Abbvie; Other Remuneration: Roche, Amgen (travel expenses).

Genentech; Stock Ownership: Hoffmann–La Roche. Boyer, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Humphrey, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Jiang, Y: Employment Leadership Position: Genentech; Stock Ownership: Genentech. Kater, A: Consultant Advisory Role: AbbVie; Honoraria: Abbvie; Research Funding: Genetech, Roche, AbbVie; Other Remuneration: Travel, accommodations, expenses: Roche.

BACKGROUND:Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear.METHODS:We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP 'group 1'; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX 'group 2'; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX 'group 3'.RESULTS:Overall, 217 patients were identified (49, 125 and 43 in groups 1-3, respectively). With median follow-up of 3.4 (range 0.2-18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1-3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5-33.1%), 6.9% (3.5-13.4%) and 2.3% (0.4-15.4%) in groups 1-3, respectively (P=0.009).CONCLUSIONS:The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

The usefulness of positron emission tomography with computed tomography (PET–CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET–CT after achieving complete metabolic response (CMR) following primary therapy. Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8–133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI⩾3. Including indeterminate scans, PET–CT retained high sensitivity 95% and specificity 97% for relapse. Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ⩾3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.

Auto-SCT remains the standard of care for younger patients with multiple myeloma. Depth of response, in particular the achievement of CR, has been shown to be important in terms of prolonging progression-free survival and, in most studies, OS.1 Theoretically, therefore, maximising depth of response during autologous transplantation is attractive. To date, no conditioning regimen has proven to be superior to high-dose melphalan (HDM),2 except tandem transplantation, in which the benefit is restricted to patients failing to achieve at least a very good PR after the first auto-SCT.1 With current induction treatment, followed by HDM-conditioned auto-SCT, only 20–30% of patients achieve CR.1 Clearly, novel strategies are required. Bortezomib is highly effective as a single agent in patients with relapsed multiple myeloma.3 It functions through a variety of mechanisms including inhibition of the NF-κB pathway, which is constitutively active in myeloma cells.4 The activated NF-κB pathway rescues cells from apoptosis induced by DNA-damaging chemotherapy, including doxorubicin and alkylating agents.5 By inhibiting NF-κB signalling, bortezomib sensitises cells to chemotherapy-induced apoptosis, including those known to be resistant to doxorubicin or melphalan.4 The synergy between bortezomib and chemotherapy is most pronounced when bortezomib is given 24 h after chemotherapy.5 Lonial et al.6 have shown the safety of bortezomib plus HDM (Bor-HDM) conditioning in up-front auto-SCT, and reaffirmed pre-clinical data that synergy is optimised when bortezomib is delivered 24 h post-melphalan. More recently, also in up-front auto-SCT, the IFM group has not only shown safety but also achieved an impressive CR rate of 32%, with 70% of patients achieving at least a very good PR.7 To our knowledge, there are no reports of Bor-HDM conditioning being used in the setting of multiply relapsed disease. Here, treatment options are limited and both haematological and non-haematological toxicity may be expected to be greater. We conducted a retrospective review of 11 consecutive, heavily pre-treated patients undergoing a total of 12 Bor-HDM-conditioned auto-SCT at Peter MacCallum Cancer Centre from January 2008 to March 2010. Patients were selected to receive this treatment because of poor overall prognosis, including multiply relapsed disease or poor-risk cytogenetics. A total of 8 of 11 patients had a previous HDM-conditioned auto-SCT. Neutrophil and platelet recovery were compared with all previous patients undergoing auto-SCT at Peter MacCallum Cancer Centre for myeloma since 2001 (n=253) and a cohort of patients who had undergone a second HDM-based auto-SCT for myeloma in the years 2001–2009 (n=33). HDM (140–200 mg/m2) was administered on D −2. Dose was reduced to 140 mg/m2 in two patients owing to renal impairment, defined as a glomerular filtration rate <30 mL/min.8 Bortezomib was administered at a dose of 1.3–1.6 mg/m2 on D −1. Stem cells were reinfused on day 0. Four patients also received post-transplant bortezomib, one on D+1, two on D+2 and one on D+1 and D+4. Comparisons were made with respect to time to platelet and neutrophil recovery, platelet and red cell transfusion requirements and non-haematological toxicity. At day 100, patients were assessed for response, as defined in the International Myeloma Working Group uniform response criteria.9 Statistical analysis was performed for platelet and neutrophil engraftment recovery times using SigmaPlot V11 (Systat Softwear Inc., Chicago, IL, USA), using t-tests for normally distributed data and Mann–Whitney Rank Sum tests for non-normally distributed data. Demographic data for patients undergoing Bor-HDM conditioning and the historical cohort undergoing a second HDM alone-conditioned auto-SCT are shown in Table 1. When compared with all HDM-conditioned auto-SCT performed since 2001, there was no difference in time to neutrophil recovery (P=0.26). There was a non-significant trend toward slower platelet recovery (P=0.13; Table 2). Moreover, when compared with the historical cohort having a second HDM-conditioned auto-SCT, there was no delay in platelet (P=0.89) or neutrophil recovery (P=0.77). Eight patients had previously been treated with the HDM-alone auto-SCT and subsequently, on relapse, went on to have a second auto-SCT conditioned with Bor-HDM. There was no significant difference in neutrophil (P=0.384) or platelet (P=0.381) recovery, while platelet and red cell transfusion requirements were similar ni the two procedures. There was no excess non-haematological toxicity when compared with HDM-conditioning alone. A total of 4 of 12 procedures were complicated by microbiologically-proven infections. Mucositis requiring total parenteral nutrition occurred during 4 of 12 procedures, which is comparable to the historical second transplant group, in which 10 of 33 patients received total parenteral nutrition. There were no deaths. At 100 days, there was a 100% overall response rate, with two CRs, one very good PR, six PRs and two minimal responses. The three patients who were never previously transplanted, each achieved a PR. At a median follow-up of 13.5 months (3.5–23), 9 of 11 patients are alive. Six patients have progressed, with a median time to progression of 7 months (5–19). Median follow-up for the remaining five patients is 5 months (3.5–14). Concordant with two earlier studies of Bor-HDM in previously untreated patients,6, 7 these results show that the addition of bortezomib to HDM for conditioning before auto-SCT in multiple myeloma is safe, with no excess non-haematological toxicity, and does not delay neutrophil or platelet engraftment even in this heavily pre-treated population. Although the primary purpose of our review was to illustrate the safety of delivery of Bor-HDM conditioning, preliminary efficacy data in our small group of heavily pre-treated patients are encouraging. Pre-clinical5 and phase I6 data indicate that the optimal timing of administration of a single dose of bortezomib is 24 h after melphalan, while the use of bortezomib post-stem cell infusion is attractive as a simple, safe method of in vivo purging. Bor-HDM conditioning can achieve an impressive response rate in up-front auto-SCT,7 however, further studies are required to determine whether it leads to deeper and more durable remissions and improved OS. The authors declare no conflict of interest.

Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6-125 months). In all, 19 cases of t-MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0-7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P=0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P=0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders.

Bortezomib added to high-dose melphalan as pre-transplant conditioning is safe in patients with heavily pre-treated multiple myeloma

INTRODUCTION: Proteasome inhibitors (PI) and histone deacetylase inhibitors (HDACi) have demonstrated synergistic pre-clinical activity in multiple myeloma (MM). The goals of this study were to evaluate this combination regimen's clinical activity and adverse events, including thrombocytopenia (TCP) since both drug classes may cause transient TCP. We performed an open label, single-centre, single-arm, phase I/II, dose-escalation trial of bortezomib, dexamethasone and romidepsin (depsipeptide) in relapsed or refractory MM. This is the first clinical trial to combine these 3 agents.

Hyper-CVAD is a dose intensive chemotherapy regimen that has been used successfully in lymphoblastic lymphoma and leukaemia. However, the effect on ovarian function has not been evaluated. Thus, we undertook a retrospective analysis of patients under 40 years of age who had Hyper-CVAD as initial therapy and documented ovarian function as defined by regular menstruation off hormonal agents or naturally conceiving. Of the 12 patients identified, 7 were evaluable. Median age was 25. Six patients had resumption of regular menstruation and three of these women have conceived naturally. In conclusion, resumption of normal fertility is probable post-treatment with Hyper-CVAD.

Purpose: Latent Epstein-Barr virus (EBV) genomes are found in the malignant cells of approximately one-third of Hodgkin's lymphoma (HL) cases. Detection and quantitation of EBV viral DNA could potentially be used as a biomarker of disease activity. Experimental Design: Initially, EBV-DNA viral load was prospectively monitored from peripheral blood mononuclear cells (PBMC) in patients with HL. Subsequently, we analyzed viral load in plasma from a second cohort of patients. A total of 58 patients with HL (31 newly diagnosed, 6 relapsed, and 21 in long-term remission) were tested. Using real-time PCR, 43 PBMC and 52 plasma samples were analyzed. Results: EBV-DNA was detectable in the plasma of all EBV-positive patients with HL prior to therapy. However, viral DNA was undetectable following therapy in responding patients (P = 0.0156), EBV-positive HL patients in long-term remission (P = 0.0011), and in all patients with EBV-negative HL (P = 0.0238). Conversely, there was no association seen for the EBV-DNA load measured from PBMC in patients with active EBV-positive HL patients as compared with EBV-negative HL, or patients in long-term remission. EBV-DNA load in matched plasma/PBMC samples were not correlated. Conclusions: We show that free plasma EBV-DNA has excellent sensitivity and specificity, and can be used as a noninvasive biomarker for EBV-positive HL and that serial monitoring could predict response to therapy. Additional prospective studies are required to further evaluate the use of free plasma EBV-DNA as a biomarker for monitoring response to treatment in patients with EBV-positive HL.

Background: The prognostic significance of marrow involvement in diffuse large cell lymphoma (DLCL) is controversial. Factors that that have been reported to influence prognosis include the pattern and extent of marrow infiltration and histological discordance between the primary site and the bone marrow. Methods: Bone marrow biopsies from 172 patients with newly diagnosed DLCL entered in two consecutive trials of the Australasian Leukaemia and Lymphoma Group were analyzed. Progression-free (PFS) and overall survival (OS) were calculated according to the absence or presence of bone marrow involvement (BMI), the extent of lymphomatous infiltration and the presence of histological discordance between the primary site and the bone marrow. Results: Of 172 patients with DLCL accrued between 1982 and 1990, who were treated with CHOP or CHOP-like regimens, 47 (27%) demonstrated marrow involvement on examination of multiple levels. Seventy two percent (34/47) of patients had discordant marrow involvement (< 50% large cells) and 28 had minimal (< 10%) involvement; these latter patients with minimal marrow involvement (< 10%) had similar PFS & OS to the 113 patients without involvement. Within the group of 47 patients with marrow involvement, an increasing percentage of BM involvement was significantly associated with an increasing percentage of concordant histology and a decreasing PFS & OS. Conclusions: Minimal BMI, seen in the majority of patients with DLCL with marrow infiltration, appears not to influence the PFS & OS. However, an increasing degree of marrow involvement is associated with an increasing component of large cells and a poorer prognosis in DLCL patients, independent of other risk factors.